Normal functioning of the nervous system depends upon the formation of vast numbers of specific connections between neurons. The mechanisms involved in producing this specificity are unknown, and their discovery presents the outstanding quest in developmental neurobiology. One key goal is to find the molecular cues which guide nerve cells during axonal growth and final target recognition. Our strategy for identifying such molecules is to first identify the genes which code for them, and then to use the methods of molecular genetics to identify the gene products. We work with 8 identified neurons in Drosophila melanogaster which are responsible for the jump and flight of the escape response. We already know much of the anatomy, physiology and connectivity of these neurons. In particular, we know the role of each individual neuron in the generation of the starting jump and the precisely repeated cycle of activation of the flight mononeurons. We are identifying the genes which specify the properties and interconnections of these cells. We have developed behavioral and physiological screens to recover mutants in which these cells are abnormally connected. We analyze the effect or the mutations by dye fills, light and electron microscopy, electrophysiology, genetic analysis (including mosaic analysis) and molecular cloning. Some of the mutants already recovered affect single branches of individual cells. For these mutations, the goal is to elucidate the role of these genes in establishing proper connectivity by visualizing the growth path of the mutant and normal neurons during development, by using mosaics to determine which cells need to express the gene, and by determining what other effects mutations in these genes have. We are doing the mapping and genetic analyses that are necessary in order to clone these genes (being done in collaborations). We will continue to screen to identify further mutations which cause these neurons to be abnormally connected in order to understand the number, specificity, mode of action and diversity of genes controlling the specificity of connectivity.